Please use this identifier to cite or link to this item: https://doi.org/10.1002/1878-0261.12146
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dc.titleX-linked inhibitor of apoptosis inhibition sensitizes acute myeloid leukemia cell response to TRAIL and chemotherapy through potentiated induction of proapoptotic machinery
dc.contributor.authorZhou, J.
dc.contributor.authorLu, X.
dc.contributor.authorTan, T.Z.
dc.contributor.authorChng, W.-J.
dc.date.accessioned2021-12-09T05:04:25Z
dc.date.available2021-12-09T05:04:25Z
dc.date.issued2018
dc.identifier.citationZhou, J., Lu, X., Tan, T.Z., Chng, W.-J. (2018). X-linked inhibitor of apoptosis inhibition sensitizes acute myeloid leukemia cell response to TRAIL and chemotherapy through potentiated induction of proapoptotic machinery. Molecular Oncology 12 (1) : 33-47. ScholarBank@NUS Repository. https://doi.org/10.1002/1878-0261.12146
dc.identifier.issn1574-7891
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/210129
dc.description.abstractAcute myeloid leukemia (AML) is an aggressive disease with an increasing incidence and relatively low 5-year survival rate. Unfortunately, the underlying mechanism of leukemogenesis is poorly known, and there has been little progress in the treatment for AML. Studies have shown that X-linked inhibitor of apoptosis (XIAP), one of the inhibitors of apoptosis proteins (IAPs), is highly expressed and contributes to chemoresistance in AML. Hence, a novel drug, RO6867520 (RO-BIR2), developed by Roche targeting the BIR2 domain in XIAP to reactivate blocked apoptosis, is a promising therapy for AML. The monotherapy of RO-BIR2 had minimal effect on most of the AML cell lines tested except U-937. In contrast to AML cell lines, in general, RO-BIR2 alone has been shown to inhibit the proliferation of primary AML patient samples effectively and induced apoptosis in a dose-dependent manner. A combination of RO-BIR2 with TNF-related apoptosis-inducing ligand (TRAIL) led to highly synergistic effect on AML cell lines and AML patient samples. This combination therapy is capable of inducing apoptosis, thereby leading to an increase in specific apoptotic cell population, along with the activation of caspase 3/7. A number of apoptotic-related proteins such as XIAP, cleavage of caspase 3, cleavage of caspase 7, and cleaved PARP were changed upon combination therapy. Combination of RO-BIR2 with Ara-C had similar effect as the TRAIL combination. Ara-C combination also led to synergistic effect on AML cell lines and AML patient samples with low combination indexes (CIs). We conclude that the combination of RO-BIR2 with either TRAIL or Ara-C represents a potent therapeutic strategy for AML and is warranted for further clinical trials to validate the synergistic benefits in patients with AML, especially for the elderly who are abstaining from intensive chemotherapy. © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
dc.publisherJohn Wiley and Sons Ltd.
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceScopus OA2018
dc.subjectacute myeloid leukemia
dc.subjectapoptosis
dc.subjectBIR2 domain
dc.subjectchemotherapy
dc.subjectTRAIL
dc.subjectXIAP
dc.typeArticle
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.contributor.departmentDEPT OF MEDICINE
dc.description.doi10.1002/1878-0261.12146
dc.description.sourcetitleMolecular Oncology
dc.description.volume12
dc.description.issue1
dc.description.page33-47
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